Download DNA Double Strand Break Repair and its Association with Inherited

Hereditary Cancer in Clinical Practice 2004; 2(1) pp. 37-43
DNA Double Strand Break Repair and its Association with Inherited
Predispositions to Breast Cancer
Rodney J. Scott
Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle and the Hunter Medical Research Institute, Newcastle,
Australia and Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia
Key words: BRCA1, BRCA2, double strand break repair, breast cancer, predisposition
Corresponding author: Rodney J. Scott, Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of
Newcastle, Callaghan NSW 2308, Australia. Phone +61 2 4921 4974, fax +61 2 4921 4253, e-mail: [email protected]
Submitted: 27 January 2004
Accepted: 10 February 2004
Abstract
Mutations in BRCA1 account for the majority of familial aggregations of early onset breast and ovarian cancer
(~70%) and about 1/5 of all early onset breast cancer families; in contrast, mutations in BRCA2 account for
a smaller proportion of breast/ovarian cancer families and a similar proportion of early onset breast cancer
families. BRCA2 has also been shown to be associated with a much more pleiotropic disease spectrum compared
to BRCA1. Since the identification of both BRCA1 and BRCA2 investigations into the functions of these genes
have revealed that both are associated with the maintenance of genomic integrity via their apparent roles in
cellular response to DNA damage, especially their involvement in the process of double strand DNA break
repair. This review will focus on the specific roles of both genes and how functional differences may account
for the diverse clinical findings observed between families that harbour BRCA1 or BRCA2 mutations.
Genomic integrity
The integrity of the genome is crucial for the correct
functioning of the individual organism. Any perturbation
that results in a loss of genomic integrity is likely to result
in disregulation and consequent uncontrolled cellular
proliferation. Maintenance of genomic integrity is
orchestrated by a number of different but interrelated DNA
repair mechanisms that include DNA mismatch repair,
nucleotide excision repair, base excision repair and DNA
double strand break repair. In relation to human neoplasia
all of these mechanisms have been implicated in disease
including such illnesses as hereditary non-polyposis
colorectal cancer (HNPCC), adenomatous polyposis,
xeroderma pigmentosum and the focus of this review,
inherited predispositions to breast cancer.
Hereditary Cancer in Clinical Practice 2004; 2(1)
There are essentially two types of genes that have
been associated with inherited predispositions to cancer,
gatekeeper genes or caretaker genes [1]. Gatekeeper
genes such as the adenomatous polyposis coli (APC)
gene can be directly associated with disease by virtue of
its involvement in the control of cell signalling pathway(s)
that are associated with cellular proliferation. Caretaker
genes, in contrast, are not involved directly with cellular
proliferation but are intimately associated with the
maintenance of genomic integrity. Loss of caretaker
function will lead to an accelerated accumulation of
change within the genome, which has the potential to
affect cellular control and hence result in accelerated
tumour development [2].
Initially it was considered that errors in genes
associated with the maintenance of genomic integrity
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Rodney J. Scott
could barely be tolerated and most resulted in severe
symptoms that culminated in the early demise of the
affected individual. Such conditions include Nijmegen
Breakage Syndrome, Ataxia Telangiectasia, Fanconi
Anaemia, Bloom’s Syndrome, Werner’s Syndrome and
Rothmund Thompson Syndrome [3]. All of these
conditions are extremely rare and are autosomal
recessive diseases that are characterised by an enormous
increase in the risk of developing malignancy. In 1993
the first hint that deficient DNA repair processes were
more common than originally believed was revealed by
the identification of the genetic basis of a relatively
common inherited predisposition to colorectal cancer,
namely HNPCC, where the underlying defect is in DNA
mismatch repair [4]. In 1994 the first gene associated
with the genetic basis of early onset breast and/or
ovarian cancer was identified (BRCA1), which at the time
could not be linked to any known cellular process [5].
Subsequently, BRCA1 has been implicated in the cellular
response to DNA double strand break damage [6].
Double strand break (DSB) repair
The mechanisms involved in the repair of DSBs are
poorly understood as they are complex and require the
accurate coordination of a large variety of proteins that
are not only involved in the process of repair but also
the recognition of repair, placing the cell cycle into
a holding pattern until the repair is complete and
transcriptional control.
Double strand breaks in DNA can be caused by
a variety of environmental insults but most notably
ionising radiation has been considered the most likely
cause of such DNA damage. There are essentially three
mechanisms of DSB, one involves nonhomologous end
joining (NHEJ) repair, another is via homologous
recombination repair (HRR) and the third is single
strand annealing (SSA). There are differences between
the three types of DSB repair in regards to the likelihood
of errors. Both NHEJ and SSA are error prone as both
mechanisms do not involve a sister chromatid in the
repair process whereas HRR is essentially error free
since this process relies on the use of the homologous
chromosome for repair [7, 8].
Initially, evidence suggested that DSBs were primarily
rejoined by NHEJ repair in mammalian cells [9]. More
recent evidence has, however, indicated that HRR is
active in mammalian cells [9] and that both mechanisms
are important for the repair of DSBs. Apart from ionising
radiation DSBs are frequently created during DNA
replication, which are under normal circumstances very
efficiently repaired via HRR [10]. Loss of either type of
38
repair process results in an increased frequency of
chromosomal rearrangements, which can result in a loss
or gain of genetic material, and/or recombination of the
genome. The repair of DSBs is a complex process and
involves not only the orchestration of a variety of proteins
but also of different DNA repair processes. DSB repair
can involve MLH1, a protein primarily involved in DNA
mismatch repair and XPD, a protein involved in
nucleotide excision repair. Furthermore, since the
identification of genes associated with rare DNA repair
disorders it has become apparent that they are
interrelated and that there is considerable overlap in
cellular phenotypes, for example Fanconi anaemia
(group B and D) is related to deficiencies in BRCA2 [11].
The repair of DSBs requires the formation of
a protein complex that involves three different proteins,
RAD50, MRE11 and NBS1 that interact with BRCA1.
A breakdown in DSB repair will result in chromosomal
rearrangements that include deletions, duplications,
inversions, and translocations. Since the genes involved
in this process are integrally linked to cell cycle checkpoint
control any perturbation in a cell ability to recognise DNA
damage may adversely affect its ability to repair DSBs,
which can result in adverse chromosomal change.
DNA damage and breast cancer
A small but significant proportion of breast cancer
patients come from families where there are other 1st
or 2nd degree relatives with disease and represents
somewhere in the order of 10% of all breast cancer
patients [12]. From this subset approximately two thirds
of them can be accounted for by mutations in the
breast cancer susceptibility genes BRCA1 or BRCA2.
It is now ten years since BRCA1 was identified and
during the intervening period much has been learnt
about the functions of both BRCA1 and BRCA2
proteins [13]. The most striking finding about the
function of the two genes has been the recognition of
their roles in either sensing DNA damage or being
intimately involved in its repair. BRCA1 and BRCA2
proteins are involved in either the recognition of DNA
DSBs or the repair of these lesions, respectively.
BRCA1
BRCA1 appears to be unique to mammals and is
likely to be relatively new in evolutionary terms as there
are no orthologs found in yeast, drosophila or c.
elegans genomes [14].
The function of BRCA1 is complex and involves
a series of proteins that have distinct binding sites on
BRCA1 (see Fig. 1) and there appears to be specific
Hereditary Cancer in Clinical Practice 2004; 2(1)
DNA Double Strand Break Repair and its Association with Inherited Predispositions to Breast Cancer
functional activity localized in different regions of the
protein. Evidence of additional proteins binding to
BRCA1 is shown in Table 1. The majority of proteins
that have been identified which interact with BRCA1
are also associated with some aspect of DNA repair
or cell cycle checkpoint control [15]. Initial studies
suggest that BRCA1 is involved in at least two types of
DSB repair, NHEJ and HRR as well as the control of
transcription [16]. A number of different facets to DNA
repair have been associated with BRCA1 and these
can be broadly categorised into those that are
intimately involved in DNA damage sensing [17], DNA
damage recognition [18], a contribution to S and G2
phase checkpoint control [19], transcriptional control
[20] and X-chromosome inactivation [21]. The
following summarises the functions that BRCA1 has
been associated with:
1. BRCA1 and RAD51 involved in focus formation.
Once a DNA break has been recognised one of the
first events that can be visualized is the formation of
foci around the DSB. Foci formation is mediated by
RPA (replication protein A), which is a multifunctional
molecule that not only functions in DSB repair but
is also required for DNA replication [22]. If cells are
irradiated RPA and BRCA1 can be observed
collocating together. In BRCA1 deficient cells the
number of damage-induced RPA foci is much
greater than that compared to their wild-type
counterparts [23].
2. BRCA1 is part of a large super protein complex
known as BASC and evidence suggests that it could
act as a damage sensor. BRCA1 appears to have
an increased affinity for branched structures
compared to double strand DNA implicated this
protein as a damage sensor [24].
3. Phosphorylation of BRCA1 suggests that it acts
as a signalling factor between damage sensing
and recognition. After DNA damage BRCA1 is
rapidly phosphorylated in dividing cells
suggesting that it may function downstream of
the checkpoint mechanisms that sense and signal
DNA damage or problems with DNA replication
during S-phase of the cell [25].
4. Routing DSB repair through HRR that are in
appropriate phases of the cell cycle [26].
5. Mediates resectioning of broken termini to
generate long single stranded tails required for
RAD51 assembly. This is mediated by activating
Chk1 kinase upon DNA damage [27].
6. During mitosis BRCA1 is clearly associated with
the centrosome, and γ-tubulin associates
preferentially with the hypophosphorylated form
of BRCA1. This suggests that BRCA1 may direct
Hereditary Cancer in Clinical Practice 2004; 2(1)
Table 1. Proteins that bind to BRCA1 or BRCA2
BRCA1
BRCA2
ATF1
BARD1
BAP1
Rb
TP53
RAD50
Mre1
Nbs1
ZBRK1
Importinα
BRAP2
γ-tubulin
STAT1
P300/CBP
BRCA2
c-Abl
RNA pol II
P/CAF
RAD51
BRAF35
DSS1
BCCIPα
EMSY
HDAC1
HDAC2
CTIP
LMO4
BACH1
ATM
ATR
c-Myc
Nmi
ERCC2
CyclinD2
Swi/Snf complex
P300
Oestrogen Receptor (ER)
a role in centrosome regulation and chromosome
segregation – an important point in relation to
the maintenance of genomic integrity and the
increase chromosomal errors observed in BRCA1
deficient cell lines [28].
7. Contribution of checkpoints in both S and G2
phases. BRCA1 is implicated in several different
checkpoint events. After ionising radiation (IR)
BRCA1 deficient cells fail to arrest scheduled
DNA synthesis in S-phase [29]. G2 arrest does
not occur in the absence of BRCA1 and it must
be phosphorylated to initiate this checkpoint [30].
Both these functions of BRCA1 are in response
to DSBs. Chromatid decatenation checkpoint
control is also deregulated [31].
8. Possible role in down regulating mRNA 3’ processing
[32].
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Rodney J. Scott
Nuclear Localization
signal
Ring Domain
Transcriptional activation
RAD50
RAD51
BRCT
TP53
BRCA2
BRCA1
HDAC1/2
BARD1
BAP1
Nbs1
c-myc
RB
importin-α
CtlP
RHA
Fig. 1. Schematic representation of the various binding sites on BRCA1 protein
Nuclear Localization
signal
BRC Repeats
Transcriptional activation
RAD51
BRCA2
EMSY
P/CAF
DSS1
Fig. 2. Schematic representation of the various binding sites on BRCA2 protein
9. Role in transcriptional control
a) interacting with proteins to remodel chromatin
structure [33]
b) transactivating genes through interaction with
TP53 [34]
c) interacting with LMO4 repressing BRCA1’s
transcriptional activation function [35]
d) acting as a co-repressor of transcription [36].
10. X-chromosome inactivation. BRCA1, BARD1 and
Xist co-localise on the inactive X-chromosome in
female somatic cells and associates with Xist RNA.
Perturbations of the relationship between BRCA1
and X-inactivation have the potential to destabilise
silencing of the X-chromosome and thereby affect
normal gene expression patterns [37].
BRCA2
Similar to BRCA1, BRCA2 is evolutionarily speaking
a relative newcomer, as it is only found in the same
genomes as BRCA1 [38]. This coupled with a high
degree of similarity in disease expression between
individuals harbouring changes in BRCA1 and BRCA2
suggests that their functions are either similar or that
40
they have unique and different functional specificity
within the overall process [38].
Less is known about the function of BRCA2 than
BRCA1. Furthermore, what is known about BRCA2 has
been gained from studies on cell lines examining
specific processes that can be observed as phenotypic
differences compared to control cells.
Does a deficiency in DSB repair orchestrated by
BRCA1 or BRCA2 result in an increased sensitivity to
ionising radiation? The evidence is as follows:
1. Linked to homologous recombination. BRCA2
directly interacts with RAD51 and they in association
with BRCA1 can be identified in nuclear foci of
undamaged replicating cells. Defective RAD51
focus formation is observed in cells where BRC
repeats are over-expressed, thereby inhibiting the
self-association of RAD51 and consequently the
formation of RAD51 nucleoprotein filaments on
single strand DNA [39].
2. Gene expression of BRCA2 is contingent on which
phase of the cell cycle the cell happens to be in.
This has lead to difficulties in determining what
Hereditary Cancer in Clinical Practice 2004; 2(1)
DNA Double Strand Break Repair and its Association with Inherited Predispositions to Breast Cancer
over-expression of BRCA2 may confer but it
appears that it may inhibit the cell cycle [40].
3. Mitotic checkpoint control. Thymic tumours from
BRCA21492Tr/Tr mice had defective mitotic checkpoint
control defects suggesting that there is
a promotion of transformed cells that develop into
malignancy [41].
4. Deficiency in the error free repair mechanism of
DSBs. BRCA2 mutant cells are phenotypically
similar to mutants of the five RAD51 paralogs
strongly implicating BRCA2 in DSB repair [42].
5. Reduced resistance to DNA-damaging agents. IR
results in an increased (1.5 – 2 fold) rate of cell
killing compared to control cells [43].
6. Missegregation of chromosomes. There is an
excess of aneuploidy in BRCA2 mutant cells caused
by anomalies in the centrosome [44].
7. Reduced levels of HRR. There are gross defects in HRR
in BRCA2 mutant cells. HNEJ is not affected [45].
8. Reduced sister chromatid exchange (SCE). SCE is
a consequence of HRR events where crossing over
occurs between sister chromatids. The rate of SCE
is reduced in BRCA2 mutant cells implying
a reduction in HRR efficiency [46].
9. Reduced efficiency of gene targeting but less than
the 20-fold difference in BRCA1 mutant cells [47].
10. Reduced numbers of RAD51 foci after IR in BRCA2
deficient cells. For HRR to occur one of the first
events is the formation of RAD51 foci. This implies
that BRCA2 is critical for the efficient formation of
this initial step in HRR [48].
the breast lobule [49-51]. Clonal expansion of any
somatic cell runs the risk of amplifying genetic errors
that may be harboured within the original set of cells.
In this way it can be envisaged that women who
harbour BRCA1 or BRCA2 germline mutations run the
risk of amplifying a ”second hit” and thereby alter the
likelihood of developing disease [52]. Since both
BRCA1 and BRCA2 are associated with genomic
integrity why is there not an increased frequency of
other malignancies in persons harbouring these
changes? There are many possibilities with respect to
the answer of this question and it should be
emphasised that at this point in time there is insufficient
knowledge about the functions of both BRCA1 and
BRCA2. Several different notions have been put forward
but none have been unequivocally supported by
experimental evidence. Evidence from one source has
indicated that BRCA1 can function as an inhibitor of
oestrogen receptor signalling [53] suggesting that in
cells deficient in this gene a loss of repression of
oestrogen mediated mammary or ovarian epithelial
proliferation occurs, thereby contributing to mammary
and ovarian carcinogenesis [54]. Other more complex
functions of BRCA1 or BRCA2 may also be tissue
specific, not necessarily as a result of some intrinsic
factor associated with only the breast or ovary but
rather as a result of the growth and differentiation
pathways of these organs [26, 55, 56].
Given the plethora of binding partners and
functions and the limited disease profiles observed in
women with mutations in BRCA1 why is there such
specificity in disease expression?
One of the most surprising results that became
rapidly apparent after the identification of BRCA1 and
BRCA2 was the absence of involvement of these genes
in breast cancer patients who had no family history of
disease (hereafter referred to as sporadic). Molecular
analysis of sporadic breast tumours revealed that
BRCA1 or BRCA2 did not behave as typical tumour
suppressor genes by virtue of the fact that there
appears to be an almost complete absence of 2nd
BRCA1 or BRCA2 allele loss. This evidence implies
that either haploinsufficiency is enough to initiate
disease or that BRCA1 or BRCA2 are not involved in
sporadic cases of breast cancer. Currently, this view
for BRCA1 remains intact whereas evidence has now
emerged implicating a novel gene product that
interacts with BRCA2 to suppress its transactivational
activity. The gene in question is termed EMSY and
when overexpressed potentially mimics the effects of
BRCA2 inactivation [57]. Whether BRCA1 will be
implicated in sporadic breast and/or ovarian cancer
remains to be determined.
Why do mutations in BRCA1 and BRCA2
result in such a specific disease pattern?
Mutations in BRCA1 and BRCA2 essentially
predispose to an increase in breast and/or ovarian
cancer although BRCA2 changes confer an increased
risk of a variety of other cancers, their relative frequency
in comparison to breast or ovarian cancer is somewhat
low. Given that the function of both genes is associated
with the maintenance of genomic integrity and that this
is a fundamental process that occurs in all cells it is
surprising to observe such disease specificity. There are
a number of possibilities that could account for the
observed disease spectrum. During breast development
at the time of puberty and again during pregnancy
rapid clonal proliferation occurs that is retained within
Hereditary Cancer in Clinical Practice 2004; 2(1)
BRCA1 and BRCA2
and sporadic breast cancer
41
Rodney J. Scott
Conclusions
There remains much to discover with respect to the
function of BRCA1 and BRCA2, notwithstanding new
mechanisms of disease are being discovered which
will eventuate in a better understanding not only of
inherited forms of breast cancer but also of sporadic
breast cancer. A thorough understanding of the events
that underlie this devastating disease will result in better
outcomes for those women unfortunate enough to
develop this malignancy.
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